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Hog1 Activation Delays Mitotic Exit Via Phosphorylation of Net1

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Hog1 Activation Delays Mitotic Exit Via Phosphorylation of Net1 Hog1 activation delays mitotic exit via phosphorylation of Net1 Silvia Tognettia,b,1, Javier Jiméneza,1,2, Matteo Viganòa, Alba Ducha,b, Ethel Queraltc, Eulàlia de Nadala,b,3, and Francesc Posasa,b,3 aDepartament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain; bInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; and cCell Cycle Group, Cancer Epigenetics and Biology Program (PEBC), L’Hospitalet de Llobregat, Institut d’Investigacions Biomèdica de Bellvitge (IDIBELL), 08908 Barcelona, Spain Edited by Douglas Koshland, University of California, Berkeley, CA, and approved March 11, 2020 (received for review October 19, 2019) Adaptation to environmental changes is crucial for cell fitness. In Finally, exit from mitosis appears to be promoted upon osmostress Saccharomyces cerevisiae, variations in external osmolarity trigger in late anaphase-arrested mutants via modulation of the release of the activation of the stress-activated protein kinase Hog1 the phosphatase Cdc14 (14). However, the effect of osmostress (high-osmolarity glycerol 1), which regulates gene expression, me- on early mitotic cells is still unclear. tabolism, and cell-cycle progression. The activation of this kinase In an unperturbed cell cycle, progression through mitosis de- leads to the regulation of G1, S, and G2 phases of the cell cycle to pends on Cdc14 (reviewed in refs. 18 and 19). The activity of prevent genome instability and promote cell survival. Here we Cdc14 is blocked from G1 to metaphase as a result of its binding show that Hog1 delays mitotic exit when cells are stressed during to the nucleolar protein Net1 (20, 21). Cdc14 release and acti- metaphase. Hog1 phosphorylates the nucleolar protein Net1, al- vation occur in two steps. The first drives Cdc14 relocalization tering its affinity for the phosphatase Cdc14, whose activity is from the nucleolus to the nucleus and depends on the activation essential for mitotic exit and completion of the cell cycle. The un- of Cdc5 (22–25) and FEAR (Cdc fourteen early anaphase re- timely release of Cdc14 from the nucleolus upon activation of lease) pathway (reviewed in refs. 18, 19, and 26). This initial Hog1 is linked to a defect in ribosomal DNA (rDNA) and telomere release is mediated by the activation of the Clb2–Cdc28 complex, segregation, and it ultimately delays cell division. A mutant of which phosphorylates Net1 on at least six sites, thereby desta- Net1 that cannot be phosphorylated by Hog1 displays reduced bilizing the Net1–Cdc14 complex (22, 27, 28). This release was viability upon osmostress. Thus, Hog1 contributes to maximizing recently reported to additionally depend on nucleolar ribosomal cell survival upon stress by regulating mitotic exit. DNA (rDNA) condensation (29). The functions of nuclear Cdc14 are essential for the establishment of a successful ana- cell cycle | mitosis | osmostress | Net1 | MAPK phase, and they include regulation of the anaphase spindle (30, 31), chromosome movements, and positioning of the anaphase – pon sudden environmental changes, cells must induce a nucleus (32) and segregation of rDNA (33 36) and telomeres Urapid and transient adaptive response to ensure survival. (37, 38). The second step, activated during late mitosis and The response to variations in extracellular osmolarity has been evolutionarily conserved, and it involves the activation of Significance mitogen-activated protein kinase (MAPK) signaling cascades. In Saccharomyces cerevisiae, the effector of the high-osmolarity Proper chromosome segregation is critical for the maintenance glycerol (HOG) pathway is the Hog1 MAPK, a functional ho- of genomic information in every cell division, which is required molog of p38 in higher eukaryotes. Upon phosphorylation, Hog1 for cell survival. Cells have orchestrated a myriad of control induces a cytoplasmatic response that acts on glycerol and ion mechanisms to guarantee proper chromosome segregation. transporters, metabolism, and translation. Additionally, Hog1 Upon stress, cells induce a number of adaptive responses to rapidly translocates into the nucleus, where it modulates tran- maximize survival that range from regulation of gene expres- scription to control gene expression and alters cell-cycle pro- sion to control of cell-cycle progression. We have found here gression (reviewed in refs. 1–3). that in response to osmostress, cells also regulate mitosis to The effect of osmostress on cell-cycle progression has been ensure proper telomeric and rDNA segregation during adap- addressed extensively in budding yeast (4–15). These studies tation. Osmostress induces a Hog1-dependent delay of cell- have unraveled a series of Hog1-dependent events that are finely cycle progression in early mitosis by phosphorylating Net1, tuned to prevent genetic instability and ensure maximal survival. thereby impairing timely nucleolar release and activation of Activation of the HOG pathway during each phase of the cell Cdc14, core elements of mitosis regulation. Thus, Hog1 acti- cycle leads to an alteration in the speed of progression, and the vation prevents segregation defects to maximize survival. mediators of this transient effect are phase-specific. Cells in G1 transiently arrest the cell cycle upon exposure to osmostress. This Author contributions: S.T., J.J., M.V., A.D., E.Q., E.d.N., and F.P. designed research; S.T., J.J., M.V., and A.D. performed research; S.T., J.J., M.V., E.Q., E.d.N., and F.P. analyzed data; and event is dependent on Hog1 in a dual manner: 1) stabilization of S.T., E.d.N., and F.P. wrote the paper. the cyclin-dependent kinase inhibitor Sic1 (10); and 2) down- The authors declare no competing interest. regulation of G1 cyclins via phosphorylation of the transcrip- This article is a PNAS Direct Submission. tion regulators Whi5 and Msa1 (10, 11, 16). The G1-to-S tran- This open access article is distributed under Creative Commons Attribution-NonCommercial- sition is also delayed via Hog1-induced transcriptional inhibition NoDerivatives License 4.0 (CC BY-NC-ND). of Clb5 (4), whereas S phase is regulated not only by delaying the 1S.T. and J.J. contributed equally to this work. accumulation of Clb5 and Clb6 (15) but also by directly acting on 2Present address: Department of Basic Sciences, Faculty of Medicine and Health Sciences, components of the replicative machinery such as Mrc1 (8). Hog1 Universitat Internacional de Catalunya, 08195 Barcelona, Spain. also impinges on the G2-to-M transition by down-regulating 3To whom correspondence may be addressed. Email: [email protected] or Clb2 expression and stabilizing Swe1, a negative regulator of [email protected]. Cdc28 whose degradation is required for entry into mitosis (5, 7, This article contains supporting information online at https://www.pnas.org/lookup/suppl/ 17). Moreover, Hog1 controls the levels of a long noncoding doi:10.1073/pnas.1918308117/-/DCSupplemental. RNA on CDC28 to facilitate cell-cycle reentry upon stress (12). First published April 7, 2020. 8924–8933 | PNAS | April 21, 2020 | vol. 117 | no. 16 www.pnas.org/cgi/doi/10.1073/pnas.1918308117 Downloaded by guest on September 24, 2021 dependent on Cdc14 nuclear localization, promotes the full re- morphogenesis) pathway, which leads to the transcriptional ac- lease of Cdc14 into the cytoplasm and relies on the MEN (mi- tivation of genes responsible for cell separation (46, 47), thereby totic exit network) (reviewed in refs. 39 and 40). As a result of ensuring timely septum disruption after cytokinesis (reviewed in MEN activation, Cdc14 is phosphorylated at sites adjacent to its refs. 48–50). nuclear localization signal and is consequently retained in the Here we show that the activation of Hog1 in metaphase leads cytoplasm (41). Cytoplasmatic Cdc14 directly promotes mitotic to delayed mitosis. This defect was not found to be linked to exit via dephosphorylation of the APC activator Cdh1, the mitotic spindle formation or elongation, or to nuclear division. In transcription factor Swi5, and the Cdc28 inhibitor Sic1. Addi- contrast, the timely release of Cdc14 was affected upon genetic tionally, cytoplasmatic Cdc14 is required for completion of mi- activation of Hog1. Hog1 phosphorylated the nucleolar protein tosis as it dephosphorylates a number of Cdc28 substrates, Net1 and thus negatively regulated Cdc14 release. Correspond- erasing the phosphorylation marks accumulated during the cell ingly, a Net1 unphosphorylatable mutant partially rescued the cycle (42–45). Among its cytoplasmatic targets, Cdc14 is also Cdc14 localization defect. Additionally, Hog1 activation resulted responsible for activating the RAM (regulation of Ace2 and in defective segregation of the late segregating regions (rDNA WT 120 A B WT 120 100 sln1ts 100 sln1ts hog1 80 80 60 60 % cells 40 40 20 20 0 0 with anaphase% cells spindle 0 101520253035405060 0 1015202530 Time after release at 37°C (min) Time after release at 37°C (min) 0 15 30 140% sln1ts 120 CELL BIOLOGY 100 80 60 % cells C 40 100 *** * NS 90 20 80 0 70 * 0 101520253035405060 60 Time after release at 37°C (min) 50 WT 40 140% sln1ts hog1 30 sln1ts 120 20 sln1ts hog1 100 % cells with released Cdc14 10 0 80 05101520 60 Time after release at 37°(min) % cells 40 010 20 0 0 101520253035405060 Time after release at 37°C (min) Control Metaphase ts Early Anaphase Metaphase Early Anaphase Late Anaphase/ Telophase hog1 sln1 ts G1 sln1 Late Anaphase/ G1 Telophase Fig. 1. Hog1 activation induces a defect in cell division and Cdc14 release in metaphase-arrested cells. (A) GAL1p-CDC20 cells were synchronized in meta- phase in YPRaff at 25 °C for 3 h and switched to 37 °C for 1 h before release upon galactose addition. Nuclear dynamics were monitored by DAPI staining. Data represent mean and SD. Representative images of the WT strain show the temporal progression of nuclear division by DAPI staining. (B) Cells were treated as in A. Mitotic spindle length was measured by immunofluorescence (α-tubulin).
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